This is a request for an ADAMHA Research Scientist Development Award (RSDA) that will enable the applicant to engage in research, on essentially a full-time basis, for an extended period (five years). By relieving the applicant of clinical responsibilities that currently occupy approximately 40% of his time, an RSDA will permit the applicant to focus on his existing research program, and afford him the time to fortify existing collaborative efforts and establish new ones. Research in the applicant's laboratory is focused on the recreational drug of abuse MDMA ("Ecstasy"), and its propensity to selectively damage brain serotonin neurons in animals and, possibly, humans. The long-term goals of this research are to better define the public health consequences of MDMA exposure, and to elucidate the role of serotonin in the central nervous system (CNS), both in health and disease. Research in this laboratory also seeks to identify the mechanism by which MDMA damages serotonin neurons~ as this information may yield insight into the processes underlying neuronal degeneration in human neurodegenerative conditions such as Alzheimer's disease and Parkinson's disease. To achieve these broad objectives, over the last 5 years, the applicant has developed a research program that is funded by four separate grants (an R29 and three ROls). This research examines the neurotoxic action of MDMA and related drugs at several levels. Studies in rodents explore mechanisms, identify critical molecular requirements for the expression of MDMA neurotoxicity, and characterize the short- and long-term responses of serotonin neurons to MDMA injury. Studies in nonhuman primates seek to more accurately gauge the risk that MDMA might pose to humans, and results from these studies are used to help direct the assessment of recreational MDMA users. Studies in humans are designed to determine whether recreational MDMA users, like MDMA-treated animals, sustain serotonergic neural injury, and if they do, to identify possible clinical consequences. Finally, PET and SPECT studies, carried out in collaboration with colleagues at the same institution, are directed toward the development of ligands that will permit imaging of brain serotonin neurons in individuals exposed to MDMA and related drugs.